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Abstract The main protease of SARS-CoV-2 (Mpro) is an important target for developing COVID-19 therapeutics. Recent work has highlighted Mpro’s susceptibility to undergo redox-associated conformational changes in response to cellular and immune-system-induced oxidation. Despite structural evidence indicating large-scale rearrangements upon oxidation, the mechanisms of conformational change and its functional consequences are poorly understood. Here, we present the crystal structure of an Mpro point mutant (H163A) that shows an oxidized conformation with the catalytic cysteine in a disulfide bond. We hypothesize that Mpro adopts this conformation under oxidative stress to protect against over-oxidation. Our metadynamics simulations illustrate a potential mechanism by which H163 modulates this transition and suggest that this equilibrium exists in the wild type enzyme. We show that other point mutations also significantly shift the equilibrium towards this state by altering conformational free energies. Unique avenues of SARS-CoV-2 research can be explored by understanding how H163 modulates this equilibrium.

Cryo-EM reveals the structure of the IgA1 metalloprotease (IgA1P) from the pathogen, G. haemolysans in the absence and presence of IgA substrate, which suggests a conserved gating mechanism for IgA1P enzymes and provides a basis for therapeutic strategies.

Pathogenic IgA1 metalloproteases block the initial host immune response by cleaving host IgA1. Using cryoEM, the authors here provide structural insights into the substrate recognition mechanism of Streptococcus pneumoniae IgA1 protease, and develop a protease-inhibiting antibody.

1 A gas-liquid chromatography (g.l.c.) method for measurement of the antidepressant nomifensine was developed and compared for precision, accuracy, sensitivity and convenience with radioimmunoassay (RIA). 2 No significant difference was found between the two techniques for unconjugated nomifensine (y = 1.07x = 2.7; r = 0.996) or total nomifensine (y = 1.;02x + 0.02; r = 0.999). 3 RIA proved more sensitive than g.l.c. (detection limit of RIA being 1 microgram/l and g.l.c. 5 micrograms/l). 4 RIA was found to be a more convenient technique (up to 50 samples per day with RIA, and 16 samples with g.l.c.). [ABSTRACT FROM AUTHOR]

1 Seven healthy volunteers received a single oral dose of 75 mg dothiepin. Plasma concentrations of dothiepin were measured by gas chromatography-mass fragmentography. 2 The plasma concentrations obtained were fitted to the equation Ct = Ae-a(t-tau) + Be-beta(t-tau) - Ce-ka(t-tau). The mean peak concentration was 47(33-71) microgram/l at 3(2-5) h. Mean estimates were as follows: absorption half life 1.2(0.07- 3.0) h, distribution half-life 2.6(1.1-3.8) h, elimination half-life 22(14-40) h, apparent volume of distribution 45(20-92) l/kg, and oral clearance 1.36(0.88-1.8) l kg-1 h-1. 3 Blood concentrations of dothiepin were measured in comparison in five of the volunteers. The mean blood/plasma ratio was 0.7(0.6-0.8). 4 Plasma and blood concentrations of northiaden and blood concentrations of dothiepin S- oxide, two metabolites of dothiepin, were also measured. Dothiepin S- oxide was the major metabolic reaching a peak level of 81(34-150) microgram/l at 5(4-6) h. In comparison, northiaden reached a peak concentration of only 10 (3-21) microgram/l at 5 (4-9) h. The mean half- life of elimination of dothiepin S-oxide was 19 (13-35) h while that for northiaden was 33 (22-60) h. [ABSTRACT FROM AUTHOR]

Background: Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder of unknown aetiology. Psychopharmacological studies have suggested a role for the neurotransmitter serotonin however further evidence for serotonin in the aetiology of OCD is conflicted. The authors used positron emission tomography (PET) to examine the binding of the dopamine D(1) receptor antagonist [(11)C]-SCH23390 to D(1) receptors in the striatum of drug-free OCD patients compared with healthy controls. Methods: Seven drug-free patients (two drug naïve) with OCD and seven age, gender and education matched healthy controls underwent positron emission tomography with [(11)C]-SCH23390. Binding Potentials (BP) at D(1) receptors were calculated for the caudate nucleus and putamen. Correlations between BP values for basal ganglia regions and clinical measures were performed in OCD patients. Results: The BP for [(11)C]-SCH23390 at D(1) receptors in OCD patients was significantly reduced in both caudate nucleus (0.59+/-0.06 vs 0.88+/-0.06, p<0.05) and putamen (0.89+/-0.06 vs 1.14+/-0.06, p<0.05) compared with healthy controls. No correlations were found between D(1) BP and symptom measures. Limitations: The main limitations of this study are the small sample size and the PET methodology which does not allow for disaggregation of Bmax and Kd values for D(1) receptor binding of [(11)C]-SCH23390. Conclusions: The finding of downregulation of D(1) receptors in the striatum of OCD patients suggests increased nigrostriatal dopaminergic drive in OCD. If confirmed, this finding provides support for trials of novel treatments in OCD based on dopaminergic system blockade. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study is to examine the efficacy of omega-3 fatty acid as an adjunct to ongoing pharmacological treatments in patients with residual symptoms of depression and anxiety., Methods/procedures: This randomized, double-blind, placebo-controlled, cross-over trial was conducted at a single private practice site. Participants were drawn from patients attending the practice.Patients meeting criteria had a 4-week run-in period where they continued to receive their prescribed medications and omega-3 supplements. Depression and anxiety ratings were assessed at recruitment and completion of the run-in phase. Patients were randomized to receive an omega-3 supplement (Neurospark) or placebo once daily for 8 weeks then crossed over to the alternative treatment. At the end of the double-blind, cross-over phase, patients received the supplement and were assessed after a 4-week run-out phase.Depression and anxiety symptoms were assessed using the Hamilton scales. Efficacy of treatment was assessed using a linear mixed model analysis with time, order of treatment, diagnosis, and their interaction as factors. Depression and anxiety scales were analyzed as independent measures., Results: The study enrolled 47 patients (mean [SD] age, 46.1 [11.2] years; [59.6%] male). Depression scores did not significantly change across assessments ( P > 0.1); there was no effect of order of treatment ( P > 0.1) or an interaction between time, order of treatment, and psychiatric diagnosis ( P > 0.1). Anxiety scores were similarly unchanged across treatment visits and order of treatment, and there was no interaction between time, order of treatment, and psychiatric diagnosis., Conclusions: Omega-3 fatty acid supplementation did not significantly alter residual symptoms in this group of patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Psilocybin is a tryptamine alkaloid found in some mushrooms, especially those of the genus Psilocybe. Psilocybin has four metabolites including the pharmacologically active primary metabolite psilocin, which readily enters the systemic circulation. The psychoactive effects of psilocin are believed to arise due to the partial agonist effects at the 5HT2A receptor. Psilocin also binds to various other receptor subtypes although the actions of psilocin at other receptors are not fully explored. Psilocybin administered at doses sufficient to cause hallucinogenic experiences has been trialed for addictive disorders, anxiety and depression. This review investigates studies of psilocybin and psilocin and assesses the potential for use of psilocybin and a treatment agent in neuropsychiatry. The potential for harm is also assessed, which may limit the use of psilocybin as a pharmacotherapy. Careful evaluation of the number needed to harm vs the number needed to treat will ultimately justify the potential clinical use of psilocybin. This field needs a responsible pathway forward.

Objective: To investigate whether diagnostic agreement and concordance between non-psychiatric (medical and surgical) doctors and consultation-liaison psychiatry changes within junior doctors' terms., Method: This was a retrospective cohort analysis of referrals from medical and surgical units to a consultation-liaison psychiatry service. Diagnostic agreement was calculated across all diagnoses and expressed as a percentage. Diagnostic concordance (expressed using Cohen's Kappa) was calculated for the two most common diagnoses of depression and delirium. Diagnostic agreement and concordance in the first two weeks (Timepoint A) were compared to those in the last two weeks (Timepoint B) of junior doctors' terms., Results: Around half the referrals (Timepoint A = 48.1%, Timepoint B = 54.0%) were excluded as no diagnosis was listed.Diagnostic agreement over all diagnoses was 31.7% (Timepoint A) and 29.9% (Timepoint B) and was not statistically different. Diagnostic concordance for depression increased from fair to moderate but was not statistically significant. Diagnostic concordance for delirium was substantial for both timepoints and were not statistically different., Conclusions: No statistically significant change in diagnostic accuracy over a junior doctors' term was found in this study.

Introduction : Major depressive disorder (MDD) remains one of the most prevalent mental health conditions. It is a chronic, relapsing condition and despite multiple treatment options, many patients fail to achieve remission of symptoms. Inadequacy of treatment has stimulated the search for agents with significant therapeutic advantages. Areas covered : This review examines literature concerning the use of desvenlafaxine in the treatment of MDD published since a previous analysis in this journal in 2014. Published papers were identified via a PubMed and Web of Science search and excluded congress presentations. Results from clinical trials in MDD, systematic reviews, and post hoc analyses in patient subgroups, are reviewed. Expert opinion : Desvenlafaxine was an effective antidepressant with favorable safety and tolerability in adults. Efficacy was demonstrated in the subgroup of peri- and post-menopausal women with MDD but not in children and adolescents. There is a relatively low potential for drug-drug interactions due to its metabolic profile. Hepatic impairment does not significantly alter dose requirements, whereas severe renal disease requires some adjustments of dose. Desvenlafaxine maybe suitable in patients with comorbid physical illnesses. Desvenlafaxine can be a first line consideration for the treatment of cases of MDD uncomplicated by medical comorbidities.

Introduction: Agomelatine is an antidepressant with unique pharmacological actions; it is both a melatonin agonist and selective serotonin antagonist. Both actions combined are necessary for antidepressant efficacy. Effects on melatonin receptors enable resynchronisation of disrupted circadian rhythms with beneficial effects on sleep patterns. Areas covered: The issue of use of an antidepressant for depression co-morbid with somatic disorders is covered by the authors. A review of the literature from 2000 to August 2018 was undertaken using Scopus and Web of Science with the key words: agomelatine, depression, medical illness. Depression in Parkinson's disease, cardiovascular illness and type II diabetes is reviewed with evidence of efficacy. Bipolar depression and seasonal affective disorder may also react favourably. Agomelatine may have specific efficacy on symptoms of anhedonia. Expert opinion: Despite approval in some major jurisdictions, the drug has failed to gain registration in the United States. A defining issue may be questions about longer term efficacy: unequivocal effectiveness in placebo-controlled relapse prevention studies has not always been demonstrated. Continuation studies suggest maintenance of clinical responsiveness. A major disadvantage of the drug is its' potential hepatotoxicity and the need for repeated clinical laboratory tests.

Few studies have investigated the effect of an acute psychosocial stress paradigm on impaired attention and working memory in humans. Further, the duration of any stress-related cognitive impairment remains unclear. The aim of this study was to examine the effect of an acute psychosocial stress paradigm, the Trier Social Stress, on cognitive function in healthy volunteers. Twenty-three healthy male and female subjects were exposed to an acute psychosocial stress task. Physiological measures (salivary cortisol, heart rate and blood pressure) and subjective stress ratings were measured at baseline, in anticipation of stress, immediately post-stress and after a period of rest. A neuropsychological test battery including spatial working memory and verbal memory was administered at each time point. Acute psychosocial stress produced significant increases in cardiovascular and subjective measures in the anticipatory and post-stress period, which recovered to baseline after rest. Salivary cortisol steadily declined over the testing period. Acute psychosocial stress impaired delayed verbal recall, attention and spatial working memory. Attention remained impaired, and delayed verbal recall continued to decline after rest. Acute psychosocial stress is associated with an impairment of a broad range of cognitive functions in humans and with prolonged abnormalities in attention and memory., (Copyright © 2014 John Wiley & Sons, Ltd.)

The novel melatonergic agonist/5-HT(2C) antagonist agomelatine displays robust antidepressant properties in humans and is active in pre-clinical models predictive of antidepressant effects. In this study, we investigated its potential influence on the locomotor hyperactivity displayed by olfactory bulbectomised rats, a putative measure of potential antidepressant activity. In addition, we compared the actions of agomelatine to those of melatonin and S32006, a selective antagonist at 5-HT(2C) receptors. Vehicle, agomelatine (10 and 50mg/kg), melatonin (10 and 50mg/kg), S32006 (0.16mg/kg to 10mg/kg) and the prototypical tricyclic antidepressant, imipramine (10mg/kg), were administered by intraperitoneal injection for 14days to male, Sprague-Dawley sham-operated and bulbectomised rats. In agreement with previous studies, imipramine was active in the model and both the lower and higher doses of agomelatine also significantly and markedly reversed the bulbectomy-induced hyperactivity to a level comparable to that seen in sham operated animals, in which agomelatine exerted no effect. Similarly the 5-HT(2C) antagonist, S32006, dose-dependently and significantly attenuated hyperactivity of bulbectomised animals, albeit with a maximal effect somewhat less marked than that of agomelatine. On the other hand, melatonin did not affect the locomotor behaviour of bulbectomised rats. The activity of agomelatine in the model is consistent with its known antidepressant properties in the clinic., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Duloxetine is a serotonin-noradrenaline reuptake inhibitor with indications for use in the short term, continuation and maintenance treatment of major depression. Although clinicians currently have access to a range of medications for the treatment of depression, a significant number of patients fail to respond or remit from their illness despite adequate trials of treatment with multiple agents. A developing concept is that antidepressant strategies that combine multiple mechanisms of action may have advantages over agents with single mechanisms (i.e., selective serotonin reuptake inhibitors). As a dual-acting agent, duloxetine offers the promise of advantages in terms of efficacy over selective serotonin reuptake inhibitors while retaining a favorable safety and tolerability profile in comparison to older agents. Likewise, duloxetine is of interest in the treatment of certain conditions commonly seen in conjunction with major depression, particularly anxiety and pain, both of which may respond more favorably to agents that act on both serotonin and noradrenaline neurotransmitter systems.

Functional neuroimaging studies in patients with obsessive-compulsive disorder (OCD) suggest there is a hyperactivation of the anterior cingulate cortex (ACC) during provocation of symptoms and conflict-inhibition tasks. Since dopamine, acting through D(1) receptors is suggested to modulate ACC activity, we hypothesised that there would be an altered D(1) binding potential (BP) in the ACC of OCD patients. Using [(11)C]-SCH23390 and positron emission tomography, we report significantly reduced D(1) BP in seven drug-free OCD patients compared with matched healthy controls. These findings suggest mesocortical dopamine inputs via D(1) receptors may play a role in the aetiology of OCD., (Crown Copyright 2010. Published by Elsevier Ireland Ltd. All rights reserved.)

Duloxetine is a serotonin-noradrenaline reuptake inhibitor with established efficacy for the short-term treatment of major depressive disorder. Efficacy in continuation treatment (greater than six months of continuous treatment) has been established from both open and placebo-controlled relapse prevention and comparative studies. Seven published studies were available for review and showed that in both younger and older populations (aged more than 65 years) the acute efficacy of duloxetine was maintained for up to one year. Response to treatment was based on accepted criteria for remission of depression and in continuation studies remission rates were greater than 70%. Comparative studies showed that duloxetine was superior to placebo and comparable to paroxetine and escitalopram in relapse prevention. Importantly a study of duloxetine in patients prone to relapse of major depressive disorder showed that the medication was more effective than placebo in this difficult to treat population. Side effects of duloxetine during continuation treatment were predictable on the basis of the known pharmacology of the drug. In particular there were no significant life-threatening events which emerged with continued use of the medication. On the other hand vigilance is required since the data base on which to judge very rare events is limited by the relatively low exposure to the drug. Duloxetine has established both efficacy and safety for continuation treatment but its place as a first-line treatment of relapse prevention requires further experience. In particular further comparative studies against established agents would be useful in deciding the place of duloxetine in therapy.

Objective: Among potential endophenotypes proposed for bipolar affective disorder focusing on circadian abnormalities associated with the illness has particularly high face validity. Melatonin sensitivity to light is one circadian endophenotype proposed as useful in bipolar disorder. The aim of this study was to investigate melatonin sensitivity to light over a range of light intensities in order to compare and contrast responses in bipolar I patients with those of healthy adult volunteers., Methods: The study included seven patients (4 females, 3 males) with bipolar I disorder and 34 control participants (22 females, 12 males) with no personal or family history of affective illness. Melatonin sensitivity to light was determined in all patients and participants across a range of light intensities (0, 200, 500 and 1000 lux)., Results: The results indicated that patients showed melatonin super-sensitivity to light in comparison with controls, a response that was consistent across the entire light intensity range investigated., Conclusion: The study provides further evidence for a super sensitive response in bipolar I patients and suggests that its potential usefulness as an endophenotypic marker of the illness is deserving of further research.

Objectives: To assess effects of a semi-acute administration of buspirone in comparison to a placebo on cognitive function and negative symptoms in patients with schizophrenia and schizoaffective disorder., Methods: In a 6-week, double-blind, placebo-controlled, independent groups study 18 subjects (14 males, four females) received in random order either placebo or buspirone (15-30 mg/day). A neuropsychological assessment using the Hopkins verbal learning test (HVLT) simple reaction time (SRT), choice reaction time (CRT), n-back spatial working memory task and the stroop colour and word test was performed at baseline and final visit. Symptom rating scales were administered at testing weeks 0, 2, 4 and 6., Results: Repeated measures ANOVA was used to examine changes in performance on tests over time. There were no statistically significant differences between placebo and buspirone treatments on either cognitive function measures or symptom ratings., Conclusion: Semi-acute adjunct treatment with buspirone may be too short to be clinically efficacious in patients with schizophrenia. Intrinsic activation of 5-HT(1A) receptors by atypical antipsychotics may hinder the ability of buspirone to further improve cognitive functions. Buspirone did not affect clinical outcomes for this chronically ill group of patients being treated with atypical antipsychotic drugs., (2009 John Wiley & Sons, Ltd.)

Objective: Clinical trials suggest between 30-50% of depressed patients have an inadequate outcome to antidepressant pharmacotherapy. Among the approaches to improve outcome has been augmentation with antipsychotic medications. We aim to investigate the efficacy and tolerability of augmentation with quetiapine in depressed patients with a partial response to antidepressants., Methods: Patients with a Major Depressive Disorder (DSMIV) who had partial/no response to a stable dose of an Selective Serotonin Reuptake Inhibitors (SSRI)/SNRI were recruited. All patients received add-on quetiapine (200-600 mg nocte) in a 6-week trial. Outcome measures (HAMD, MADRS) were assessed at screening, baseline, weeks 1, 2, 4 and 6. Extrapyramidal symptoms (EPSEs) were assessed at baseline, weeks 2, 4 and 6. A neuropsychological battery of tests was administered at baseline, weeks 3 and 6., Results: Nineteen patients entered the trial and 18 completed the trial per protocol. We report a rapid improvement in depression ratings over 6 weeks (p < 0.0005) and remission rates of 67% at week 1 and 94% at week 6. There was no evidence of EPSE and no worsening (and some improvement) of cognition., Conclusion: This suggests clinical benefits of quetiapine augmentation of SSRI/SNRI antidepressants with no worsening, and possible improvements in cognition.

Duloxetine, a medication with effects on both serotonin and noradrenaline transporter molecules, has recently been approved for the treatment of generalized anxiety disorder. The evidence for its efficacy lies in a limited number of double blind, placebo controlled comparisons. Statistically significant improvements in the Hamilton Anxiety Rating Scale from baseline were demonstrated in all studies at doses of 60 to 120 mg per day. The significance of such changes in terms of clinical improvements compared to placebo is less certain, particularly when the effect size of the change is calculated. In comparative trials with venlafaxine, duloxetine was as effective in providing relief of anxiety symptoms. In addition to improvements in clinical symptoms duloxetine has also been associated with restitution of role function as measured by disability scales. Duloxetine use is associated with nausea, dizziness, dry mouth, constipation, insomnia, somnolence, hyperhidrosis, decreased libido and vomiting. These treatment emergent side effects were generally of mild to moderate severity and were tolerated over time. Using a tapered withdrawal schedule over two weeks in the clinical trials, duloxetine was associated with only a mild withdrawal syndrome in up to about 30% of patients compared to about 17% in placebo treated patients. Duloxetine in doses of up to 200 mg twice daily did not prolong the QTc interval in healthy volunteers. Like other agents with dual neurotransmitter actions duloxetine reduces the symptoms of generalized anxiety disorder in short term treatments. Further evidence for its efficacy and safety in long term treatment is required.

The secretion of the hormone melatonin is particularly robust to the effect of pharmacological agents. Medications may alter melatonin levels through either altering adrenergic activity or affecting liver enzymes involved in melatonin metabolism. The aim of this study was to investigate the effect of venlafaxine, a third generation antidepressant with known adrenergic properties on melatonin secretion. A further aim of the study was to investigate the correlation between plasma and salivary measures on this medication. Eight healthy adult participants (four males, four females) took part in this double blind placebo controlled randomised trial. Participants were tested on 3 nights after taking venlafaxine XR (75 mg), venlafaxine IR (75 mg) or placebo. Participants were placed in a darkened room between 1900 and 0300 h and regular temperature readings, blood and saliva samples were drawn to assess melatonin and cortisol secretion in each condition. There was no significant effect of venlafaxine IR or XR on melatonin concentrations in plasma or saliva and no effects on other circadian parameters including cortisol and temperature. It was notable that the correlation between plasma and salivary melatonin levels became poor after drug treatment. These results indicate that at low doses the mixed serotonergic and noradrenergic drug venlafaxine has no effect on nocturnal melatonin concentrations., ((c) 2008 John Wiley & Sons, Ltd.)

Cognitive impairments in schizophrenia have been recognized as a prominent feature of the illness. Research is now focusing on determining a relationship between neurocognitive impairments, and social and functional outcome. Despite a number of comprehensive reviews on neurocognitive measures and reports on spatial working memory abnormalities in patients with schizophrenia when compared to healthy volunteers, there have been no meta-analyses of the extent of the abnormality in this group of patients. We reviewed 33 studies (from 1992 to 2005) on spatial working memory impairment in schizophrenia with the aim of providing a quantitative assessment of the consistency and the magnitude of the deficit. From the quantitative data analysis, it is evident that patients with schizophrenia are consistently more impaired on the spatial working memory measures than healthy controls. These impairments may be related to social disability and explain some cognitive deficits that characterize the clinical presentation of schizophrenia.

Antidepressant drugs were introduced into clinical practice in the mid-20th Century. While for the most part they have proven effective for the amelioration of depressive symptoms, they are associated with significant deficiencies. These well-recognized shortcomings have given impetus to the pursuit of new molecules that seek to improve on the efficacy, tolerability and safety of existing medications. The following article reviews several new compounds that may have antidepressant potential. Some are more advanced in development, having undergone clinical trials, whereas the clinical potential of others is yet to be explored. For this latter group of compounds, the antidepressant potential relies on their activity in validated animal models. Agomelatine and duloxetine are in the first category, having shown antidepressant efficacy in clinical trials. The blockade of cortisol secretion continues to be a focus of attention for the development of new antidepressants. Thus, synthesis inhibitors, nonpeptide antagonists of corticotropin-releasing factor and glucocorticoid receptor antagonists show some promise in clinical and preclinical tests. Antagonists of the neuropeptide substance P, vasopressin and neuropeptide Y represent a departure of approach from traditional monoamine receptor-based mechanisms. While the clinical results with one substance P antagonist have led to the cessation of further trials, other molecules are in development. Approaches to treatment based on glutamatergic transmission arose from observations in animal models. The clinical evaluation of such compounds awaits further development. The extent to which new agents can be judged to have met the goals of efficacy, tolerability and safety rely not only acute treatment trials but also on longer-term outcomes and postmarketing surveillance. Whether any of the new agents canvassed here prove to be significantly better than existing agents is clearly a judgement for the future.

Background and Aim: Patients in the intensive care unit often suffer from lack of sleep at night. We hypothesised that nocturnal melatonin may increase observed nocturnal sleep in tracheostomised patients., Design: Double-blind, randomised, placebo-controlled pilot study., Setting: ICU of a tertiary hospital., Participants: Thirty-two ICU patients with tracheostomy who were not receiving continuous sedation., Methods: We administered either oral melatonin (3mg) or placebo at 20:00. We collected pre- and post-dosage blood samples on Days 1 and 3 to confirm drug delivery. Primary outcome measure was number of hours of observed sleep at night, assessed by the bedside nurse. Secondary outcome measures included comparison of the incidence of agitation, assessed by score on the Riker Sedation-Agitation Scale, and requirement for sedatives or haloperidol to settle agitation., Results: Pre-treatment melatonin levels in the two groups were similarly low: 4.8 pg/mL (95% CI, 2.4-7.5) for melatonin versus 2.4 (95% CI, 1.6-3.2) for placebo (P=0.13). Post-treatment, melatonin levels increased significantly in the melatonin group compared with the placebo group (3543 pg/mL versus 3 pg/mL; P<0.0001). However, subsequent observed nocturnal sleep was similar in the two groups: 240 minutes (range, 75-331.3) for melatonin v 243.4 minutes (range, 0-344.1) for placebo (P=0.98). Observed diurnal sleep was also similar: 138.7 minutes (range, 50-230) with melatonin v 104 minutes (range, 0-485) for placebo (P=0.42). The incidence of agitation was non-significantly higher in the melatonin group (31% v 7%; P=0.11), while the requirement for extra sedation or use of haloperidol was slightly higher in the placebo group (57% versus 46%; P=0.56)., Conclusion: Melatonin is well absorbed, and a standard dose increases blood levels approximately 1000-fold. However, in this pilot assessment, these high levels failed to increase observed nocturnal sleep or induce other observable benefits in tracheostomised ICU patients.

The super-sensitivity of the neurohormone melatonin to light in patients with bipolar disorder provides evidence of the circadian nature of the disorder. This response has been proposed as an endophenotype for identifying people at risk of the disorder and guiding investigations of molecular genetic targets. However, before this response is used as an endophenotypic marker, the heritable nature of melatonin sensitivity in the normal population must be established. The aim of this study was to investigate the heritability of nocturnal melatonin secretion and sensitivity to light in monozygotic and dizygotic twins with no psychiatric history. This study investigated overall melatonin levels (between 2000 and 2400 h) and suppression by 500 lx of light (between 2400 and 0100 h) in 20 pairs of twins (nine monozygotic, 11 dizygotic). The results indicate that melatonin secretion is highly heritable with secretion in one twin being a significant predictor of secretion in their twin in both monozygotic and dizygotic pairs. In relation to light sensitivity, genetic loading appears to play a significant role with the greatest concordance between monozygotic twins, followed by dizygotic twins and finally low concordance in unrelated individuals. This provides additional support for the usefulness of melatonin sensitivity to light as a potential endophenotypic marker of bipolar affective disorder.

Antidepressant drugs represent the principal form of treatment for major depressive disorder. While there are a plethora of medications available for this task, current drugs have many shortcomings. In the face of these deficiencies there is an ongoing search for new agents. The search has been guided, in part, by drug design based on existing agents and their putative mechanism of action. This has been less than fruitful in addressing inadequacies of existing medications as it has not produced compounds which are novel in terms of pharmacological mechanisms. Recent insights from molecular biological approaches hold promise for the discovery of novel compounds, in particular the so-called neurogenesis hypothesis suggests novel therapeutic approaches. Although significantly modified over the years, the monoamine hypothesis of depression and antidepressant drug action still remains an important driving force behind the development of new compounds. Several recently marketed agents and some in early-phase development tend to conform to these existing mechanistic hypotheses. Clearly the place of these agents in the treatment of depression is dependent on issues such as short- and long-term safety and efficacy. Duloxetine has been developed as a dual monoamine re-uptake inhibitor. Agomelatine is a compound with major effects on the circadian system as well as effects on subtypes of the serotonin receptor system. While the mechanism of action of this compound is not certain, recent evidence would suggest that the drug exerts its effects through antagonist actions at serotonin receptors. Compounds based on the hypothalamic pituitary adrenal axis, substance P antagonism and other neuropeptides have potential application for the treatment of depression but require further development before that potential is realized.

This prospective 6-week study examined the differences in dosage and steady state plasma concentrations of sertraline in Chinese versus Caucasian depressed patients. Two groups of Chinese patients from different geographical sites and a group of Caucasian patients were evaluated with clinical measures during an initial dose of 50 mg/day, with subsequent doses adjusted clinically. The results of 17 Australian Chinese (ACHI), 13 Malaysian Chinese (MCHI) and 15 Australian Caucasians (AC) were analysed. Despite controlling for weight, the AC subjects received a significantly higher dose than both the ACHI (P = 0.002) and the MCHI groups (P = 0.012). However, the mean sertraline concentration to dose ratios at weeks 1 and 6 were not significantly different between the three groups. Sertraline was effective and well tolerated in both ethnic groups with few adverse events. Although there was a lack of difference between groups in the pharmacokinetic results, Chinese depressed patients appeared to require lower dosages with consequently lower plasma concentrations of sertraline compared to Caucasian patients to achieve clinical efficacy. Further studies of the dosages, kinetics and adverse effects of selective serotonin reuptake inhibitors linked with genotyping are necessary.